The goal of our research program is to understand the mechanisms by which specific gene control susceptibility of inbred mice to hepatocarcinogenesis. These studies will provide insights into the functions of critical regulatory pathways for multistage hepatocarcinogenesis and paradigms for understanding the action of risk- modifier genes in humans. We have identified and mapped three genes that determine the high susceptibilities of C3H, CBA and C57BR mice to liver tumor induction relative to C57BL/6 mice. The Hcs locus, carried by C3H and CBA is located on Chromosome 1. The Hcf1 locus, on Chromosome 17, and the Hcf2 locus, on Chromosome 1, are responsible for the uniquely high susceptibility of female C57BR mice to hepatocarcinogenesis. The goal of the first two aims of the present application is to determine the molecular identities of these genes by first mapping them to high resolution by analysis of congenic strains that carry the susceptible allele on a C57BL/6 background and then to use that positional information to molecularly clone the genes. In the third aim, we seek to understand the mechanistic basis for the sexual dimorphism observed in murine hepatocarcinogenesis. Specifically, we will test the hypothesis that sex- dependent differences in the growth hormone regulation are responsible for the increased sensitivity of male mice to liver tumor induction relative to female mice. The fourth aim focuses on the genetic basis for strain variation in the biological consequences of one class initiating event for hepatocarcinogenesis, mutational activation of the Hras1 gene. We will attempt to map genes carried by SM mice that suppress this pathway and to determine whether these genes act by tissue specific or cell autonomous mechanisms.